LFTs:
Enzyme tests: AST (formerly known as SGOT), ALT (formerly known as SGPT), Alkaline phosphatase, and Gamma glutamyl transpeptidase
Synthetic function: Serum albumin, PT
Ability to detoxify: Serum bilirubin, which measures the liver's ability to detoxify metabolites and transport organic anions into bile.
History:
Exposure to any chemical or medications (prescription, OTC, and herbal) which may be temporally related to the onset of LFT abnormalities
The duration of LFT abnormalities
Any accompanying symptoms such as jaundice, arthralgias, myalgias, rash, anorexia, weight loss, abdominal pain, fever, pruritus, and changes in the urine and stool.
A history of arthralgias and myalgias before onset of jaundice, suggests viral or drug-related hepatitis.
A history of jaundice associated with the sudden onset of severe right upper quadrant pain and shaking chills suggests choledocholithiasis and ascending cholangitis.
Blood transfusions, IVDA, intranasal drug use, tattoos, and sexual activity.
Recent travel history, exposure to people with jaundice, exposure to possibly contaminated foods, occupational exposure to hepatotoxins, and alcohol consumption.
Physical Examination:
Temporal and proximal muscle wasting suggest longstanding diseases.
Stigmata of chronic liver disease include spider nevi, palmar erythema, gynecomastia, caput medusae, Dupuytren's contractures, parotid gland enlargement, and testicular atrophy are commonly seen in advanced Laennec's cirrhosis and occasionally in other types of cirrhosis.
An enlarged left supraclavicular node (Virchow's node) or periumbilical nodule (Sister Mary Joseph's nodule) suggest an abdominal malignancy.
Jugular venous distension, a sign of right sided heart failure, suggests hepatic congestion
A right pleural effusion, in the absence of clinically apparent ascites, may be seen in advanced cirrhosis
Check the liver span in MCL, feel the edge of liver below the right costal margin. Feel consistency of the liver, the size of the spleen.
Ascites (usually by determining whether there is a fluid wave or shifting dullness).
Patients with cirrhosis may have an enlarged left lobe of the liver (which can be felt below the xiphoid) and an enlarged spleen (which is most easily appreciated with the patient in the right lateral decubitus position).
A grossly enlarged nodular liver or an obvious abdominal mass suggests malignancy.
Enlarged tender liver could be viral or alcoholic hepatitis or, less often, an acutely congested liver secondary to right-sided heart failure.
Severe right upper quadrant tenderness with respiratory arrest on inspiration (Murphy's sign) suggests cholecystitis or, occasionally, ascending cholangitis.
Ascites in the presence of jaundice suggests either cirrhosis or malignancy with peritoneal spread.
Laboratory tests:
Critical step in guiding the evaluation is determining the overall pattern of the abnormal LFTs, which can be broadly divided into two categories:
Hepatocellular pattern. Elevation in the serum AST/ALT compared with the alkaline phosphatase
Cholestatic pattern. Elevation of alkaline phosphatase compared with AST/ALT.
Serum bilirubin can be prominently elevated in both hepatocellular and cholestatic conditions and therefore is not necessarily helpful in differentiating between the two.
Assess liver function. Serum albumin and PT. A low albumin suggests a chronic process such as cirrhosis or cancer, while a normal albumin suggests a more acute process such as viral hepatitis or choledocholithiasis. An elevated prothrombin time indicates either vitamin K deficiency due to prolonged jaundice and malabsorption of vitamin K or significant hepatocellular dysfunction. The failure of the prothrombin time to correct with parenteral administration of vitamin K indicates severe hepatocellular injury.
Bilirubinuria reflects direct hyperbilirubinemia and therefore underlying hepatobiliary disease. In contrast to conjugated bilirubin, unconjugated bilirubin is tightly bound to albumin; as a result, it is not filtered by the glomerulus and present in the urine unless there is underlying renal disease.
Conjugated bilirubin may be found in the urine when the total serum bilirubin concentration is normal because the renal reabsorptive capacity for conjugated bilirubin is low and the methods used can detect urinary bilirubin concentrations as low as 0.05 mg/dL (0.9 mmol/L). Thus, bilirubinuria may be an early sign of liver disease.
Common Patterns of LFT abnormalities:
Decision to pursue specific testing should be guided by the pretest probability of the underlying liver disease, the pattern of abnormalities, and suggestive features obtained from the history and physical examination.
Step 1
Review possible link to medications (NSAIDs, statins, Abx. antiepileptic drugs, and anti-tuberculous drugs, APAP; herbal therapies or recreational drugs
Screen for alcohol abuse (screening instruments, AST/ALT ratio >2:1).
A twofold elevation of the gamma glutamyltransferase (GGT) in patients whose AST to ALT ratio is greater than 2:1 strongly suggests alcohol abuse. However, an elevated GGT by itself is insufficiently specific to establish the diagnosis.
It is rare for the AST to be greater than eightfold elevated and even less common for the ALT to be greater than fivefold elevated. The ALT may even be normal even in patients with severe alcoholic liver disease.
Obtain serology for hepatitis B and C (HBsAg, HBsAb, HBcAb, HCV Ab)
Screen for hemochromatosis (FE/TIBC >45 percent)
Evaluate for fatty liver (AST/ALT usually < 1, obtain a RUQ ultrasound)
Step 2: If the above is unrevealing
Exclude muscle disorders (obtain creatinine kinase or aldolase)
Obtain thyroid function tests (TSH if hypothyroidism is suspected otherwise obtain TSH, serum free T4 and T3 concentrations)
Consider celiac disease (especially in patients with ahistory of diarrhea or unexplained iron deficiency - serum antiendomysial IgA or anti tissue transglutaminase IgA antibodies arereasonable screening tests)
Consider adrenal insufficiency
Step 3: Consider less common causes of liver disease
Consider autoimmune hepatitis particularly in women and those with a history of other autoimmune disorders (check serum protein electrophoresis, obtain ANA and ASMA if positive)
Consider Wilson's disease in those <40 (check serum ceruloplasmin, evaluate for Kayser Fleischer rings)
Consider alpha-1-antitrypsin deficiency especially inpatients with a history of emphysema out of proportion to their age orsmoking history (obtain alpha-1-antitrypsin phenotype)
Step 4: Obtain a liver biopsy or observe
Observe if ALT and AST are less than two-fold elevated
Otherwise consider a liver biopsy
Mild is defined as <250 U/L, chronic is defined as more than six months.
ALT is an enzyme, a.k.a SGPT. High conc occur in the liver, and relatively low conc are found in heart, kidney, and muscle. Values are higher in black and male. Avoid hemolysis during collection as ALT activity is 6 times higher in RBCs.
Increased ALT levels are found in the following conditions: Hepatocellular disease, alcoholic cirrhosis, metastatic cirrhosis, metastatic liver tumor, obstructive jaundice, viral, infectious, or toxic hepatitis, infectious mononucleosis, pancreatitis, MI, Heart failure, polymyositis, severe burns, trauma to striated muscle, severe shock.
ALT > AST = acute extrahepatic biliary obstruction.
AST/ALT ratio is high in alcoholic liver disease. ALT is more specific than AST for liver disease, but the AST is more sensitive to alcoholic liver disease.
Alcohol-acetaminophen syndrome: extremely high level of ALT/AST values are found >9000 U/L: this extreme level can distinguish this syndrome from alcoholic or viral hepatitis.
Salicylates, heparin (therapeutic doses), hemolysed blood, obesity.
AST is an enzyme, a.k.a SGOT. Present in tissues of high metabolic activity. Used to evaluated liver disease.
Increased AST: MI (4-10xnl), acute hepatitis, chronic hepatitis (ALT > AST), active cirrhosis (drug induced or alcohol induced: AST > ALT); infectious mononucleosis, hepatic necrosis and metastases. primary or metastatic carcinoma, alcoholic hepatitis, Reye's syndrome.
Other causes: hypothyroidism, trauma and irradiation to skeletal muscle, dermatomyositis, polymyositis, TSS, C. cath, recent brain trauma with brain necrosis, cerebral infarction, crushing and traumatic injuries, head trauma, surgery, progressive muscle dystrophy, pulmonary emboli, lung infarction, gangrene, malignant hyperthermia, mushroom poisoining, shock, hemolytic anemia, exhaustion, heat stroke.
Hepatitis B surface antigen
Hepatitis B surface antibody
Hepatitis B core antibody
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Patients who are HBsAg and HBcAb are chronically infected and additional testing with HBeAg, HBeAb, and HBV-DNA is indicated.
A positive HBsAb and HBcAb indicates immunity to hepatitis B and another cause of aminotransferase elevation should be sought.
The presence of a positive HBV DNA, +/- HBeAg indicates viral replication.
A positive HBV DNA and a negative HBeAg indicates that the patient has a precore mutant of hepatitis B. Both of these situations warrant further evaluation with a liver biopsy and possible treatment.
A positive HBsAg with a negative HBV DNA and a negative HBeAg suggests that the patient is a carrier of hepatitis B and in a non-replicative state. The presence of a carrier state does not explain elevated aminotransferases and another cause needs to be sought.
Chronic hepatitis C is very common in the United States and other parts of the world. The risk is highest in individuals with a history of parenteral exposure (blood transfusions, intravenous drug use, occupational), cocaine use, tattoos, body piercing, and high risk sexual behavior.
Initial test for hepatitis C is the hepatitis C antibody.
A positive hepatitis C antibody in a patient with risk factors for the infection is sufficient to make the diagnosis and a quantitative hepatitis C RNA, hepatitis C genotype, and liver biopsy should next be done to assess the patient's need and suitability for treatment.
A positive hepatitis C antibody in a low-risk patient should be verified with either a RIBA or a qualitative PCR test.
A negative hepatitis C antibody in a patient with risk factors for hepatitis C should be verified with a qualitative PCR test.
Hereditary hemochromatosis — Hereditary hemochromatosis (HHC) is a common genetic disorder.
Screening should begin with a serum iron and total iron binding capacity (TIBC).
Calculate the iron or transferrin saturation (serum iron/TIBC).
> 45%, get a serum ferritin level.
Ferritin should not be obtained as an initial test because it is an acute phase reactant and therefore less specific than the iron saturation.
A serum ferritin concentration of greater than 400 ng/mL in men and 300 ng/mL in women further supports the diagnosis of HHC.
A liver biopsy should be performed if screening tests suggest iron overload to quantify hepatic iron and to assess the severity of liver injury, and genetic testing should be done.
A hepatic iron index (hepatic iron concentration in micromoles per gram dry weight divided by the patient's age) greater than 1.9 is consistent with homozygous HHC.
A liver biopsy is not necessary for patients less than 40 years of age with genotypically defined hemochromatosis (C282Y homozygous) with normal liver function tests.
Not every patient who is homozygous for the HFE mutation has iron overload and not every patient with HHC has the identified HFE mutation. Thus, the biopsy may still be required to identify iron overload in some patients and is critical to determine the amount of fibrosis. Patients with HHC and cirrhosis continue to have a high risk of developing hepatocellular carcinoma even with depletion of body iron stores. These patients need to be identified and screened appropriately.
Hepatic steatosis and steatohepatitis — Hepatic steatosis and an associated condition, non-alcoholic steatohepatitis (NASH), may present solely with mild elevations of the serum aminotransferases, which are usually less than fourfold elevated. NASH is a condition more common in women and associated with obesity and type 2 diabetes mellitus. In contrast to alcohol related liver disease, the ratio of AST to ALT is usually less than one.
The initial evaluation to identify the presence of fatty infiltration of the liver is radiologic imaging including ultrasound, computed tomographic imaging, or magnetic resonance imaging. Ultrasonography has a lower sensitivity than CT or MRI scanning, but is less expensive. Thus, in a patient in whom there is a high pretest probability of steatosis and tests for hepatitis B, C, and HHC are unremarkable, the least expensive test to look for steatosis is ultrasonography. However, radiologic imaging cannot identify inflammation. Thus, the differentiation between steatosis and NASH requires a liver biopsy. Nevertheless, because of the absence of effective medical therapy for NASH, we do not advocate a liver biopsy unless one of the following are present:
Peripheral stigmata of chronic liver disease
Splenomegaly
Cytopenia
Abnormal iron studies
Diabetes and/or significant obesity in an individual over the age of 45
Step two — The next set of tests should look for non-hepatic causes of elevated aminotransferases, which include principally muscle disorders and thyroid disease. Much less common causes are occult celiac disease and adrenal insufficiency.
Muscle disorders — Elevated serum aminotransferases may be caused by disorders that affect organs other than the liver, most commonly striated muscle. Serum AST and ALT may both be elevated with muscle injury. Their ratio depends in part upon when they are assessed relative to the muscle injury. Immediately after muscle injury, the AST/ALT ratio is generally greater than three, but approaches one within a few days because of a faster decline in the serum AST. Peak AST and ALT levels are variable. In one series, peak AST levels range from as low as 235 IU to as high as 10,000 IU while peak ALT ratios range from as low as 115 IU/L to as high as 850 IU/L
Conditions that can cause this include subclinical inborn errors of muscle metabolism, acquired muscle disorders such as polymyositis, seizures, and heavy exercise such as long distance running. If striated muscle is the source of increased aminotransferases, serum levels of creatine kinase, LDH, and aldolase will be elevated at least to the same degree. The creatine kinase or aldolase levels should be determined if other more common hepatic conditions have been ruled out
Thyroid disorders — Thyroid disorders can produce elevated aminotransferases by unclear mechanisms. A TSH is a reasonable screening test for hypothyroidism while a full set of thyroid function tests should be checked if hyperthyroidism is suspected.
Celiac disease — Several reports have described elevated serum aminotransferases in patients with undiagnosed celiac disease. The cause is uncertain. In one report, the serum AST ranged from 29 to 80, and the serum ALT ranged from 60 to 130 with the ALT usually slightly greater than AST. Serum aminotransferases returned to normal in all but one patient one year following a gluten free diet. The diagnosis is suggested by appropriate antibody screening with serum antiendomysial IgA or anti tissue transglutaminase IgA antibodies
Adrenal insufficiency — Aminotransferase elevation (1.5 to 3 times the upper limit of normal) has been described in patients with adrenal insufficiency (due to Addison's disease or secondary causes), including those without obvious clinical features of the disorder [26-28]. Aminotransferases normalize within one week following appropriate treatment.
Anorexia nervosa — Anorexia nervosa has been associated with aminotransferase elevation by mechanisms that are not well understood. In a series of 214 women, 12 percent had aminotransferase elevation [29]. In another series, elevated serum aminotransferases were associated with lower body temperature and pulse rate and a lower BMI [30]. Profound serum aminotransferase elevation associated with liver dysfunction has been described in case reports [31-34].
Step three — The next set of tests is aimed at identifying rarer liver conditions.
Autoimmune hepatitis — Autoimmune hepatitis (AIH) is a condition found primarily in young to middle-aged women. The diagnosis is based upon the presence of elevated serum aminotransferases, the absence of other causes of chronic hepatitis, and features (serological and pathological) suggestive of AIH. (See "Clinical manifestations and diagnosis of autoimmune hepatitis".)
A useful screening test for AIH is the serum protein electrophoresis (SPEP). More than 80 percent of patients with autoimmune hepatitis will have hypergammaglobulinemia. A greater than twofold polyclonal elevation of the immunoglobulins supports the diagnosis. Additional tests commonly ordered include antinuclear antibodies (ANA), anti-smooth muscle antibodies (SMA), and liver-kidney microsomal antibodies (LKMA). ANA and SMA have reported sensitivities of 28 and 40 percent, respectively. LKMA positive autoimmune hepatitis is rare in the United States, Australia, and Japan. (See "Measurement and clinical significance of antinuclear antibodies".)
A reasonable approach to diagnosing autoimmune hepatitis is to start with an SPEP. An ANA and SMA should be obtained in patients who have a polyclonal increase in gamma globulin. Elevated gamma globulins and high titer autoantibodies should prompt a liver biopsy to confirm the diagnosis of AIH. Patients (especially young women) with negative viral serologies and persistently elevated aminotransferases greater than 100 u/L should undergo liver biopsy even in the absence of elevated gamma globulins and autoantibodies. If the biopsy is consistent with chronic active hepatitis, patients should receive a trial of corticosteroids since approximately 20 percent of patients with steroid responsive hepatitis will not have a positive ANA or SMA at the time of presentation [35].
Wilson's disease — Wilson's disease, a genetic disorder of biliary copper excretion, may cause elevated aminotransferases in asymptomatic patients. While the prevalence of Wilson's disease is very low, it is a treatable liver disease and needs to be identified. (See "Diagnosis of Wilson disease".)
Patients usually present between ages 5 to 25, but the diagnosis should be considered in patients up to the age of 40. However, the range of ages in cases reports spans from age 3 to 80 The initial screening test for Wilson's disease is a serum ceruloplasmin, which will be reduced in approximately 85 percent of patients. Patients should also be examined by an ophthalmologist for Kayser-Fleischer rings. If the ceruloplasmin is normal and Kayser-Fleischer rings are absent, but there is still a suspicion of Wilson's disease, the next test is a 24-hour urine collection for quantitative copper excretion. A value of greater than 100 mcg/day is suggestive of the diagnosis. (See "Patient information: Collection of a 24-hour urine specimen".)
The diagnosis is usually confirmed by a liver biopsy for quantitative copper. Patients with Wilson's disease have liver copper levels of greater than 250 mcg/gm of dry weight. While the gene responsible for Wilson's disease has been identified, the number of disease specific mutations is so great that molecular diagnosis is not yet feasible except in family members of a proband with a known mutation.
Alpha-1 antitrypsin deficiency — Alpha-1 antitrypsin deficiency is an uncommon cause of chronic liver disease in adults. Decreased levels of alpha-1 antitrypsin can be detected either by direct measurement of serum concentrations or by the absence of the alpha-1 peak on a serum protein electrophoresis. However, serum concentrations of alpha-1 antitrypsin can be increased in response to inflammation resulting in a falsely negative test. As a result, obtaining an alpha-1 antitrypsin phenotype is probably the most cost-effective test. In adults, alpha-1 antitrypsin deficiency should be suspected in patients who have a history of emphysema either at a young age or out of proportion to their smoking history. (See "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency".)
Step four — A liver biopsy is often considered in patients in whom all of the above testing has been unyielding. However, in some settings, the best course may be observation.
Whom to observe — We recommend observation only in patients in whom the ALT and AST are less than twofold elevated and no chronic liver condition has been identified by the above noninvasive testing. This approach was supported by a preliminary study in which expectant clinical follow-up was found to be the most cost-effective strategy for managing asymptomatic patients with negative viral, metabolic, and autoimmune markers and chronically elevated aminotransferases [36]. Another study included 36 patients with a chronic elevation of the serum ALT, AST, or alkaline phosphatase (50 percent or greater above normal) [37]. Patients with a strong suspicion for a particular liver disease were excluded. The remainder underwent a liver biopsy, which changed the diagnosis in only 5 patients and influenced treatment in 12 patients, 10 of whom were offered investigational therapy. The authors concluded that the biopsy results only infrequently clarified the presumptive diagnosis and that no proven therapy exists for many such patients.
Whom to biopsy — We recommend a liver biopsy in patients in whom the ALT and AST are persistently greater than twofold elevated. While it remains unlikely that the biopsy will provide a diagnosis or lead to changes in management, it is often reassuring to the patient and physician to know that there is no serious disorder.
ISOLATED HYPERBILIRUBINEMIA — Isolated hyperbilirubinemia occurs principally in two settings: (see "Bilirubin metabolism").
Overproduction of bilirubin
Impaired uptake, conjugation, or excretion of bilirubin
The initial step in evaluating a patient with an isolated elevated hyperbilirubinemia is to fractionate the bilirubin to determine whether the hyperbilirubinemia is predominantly conjugated or unconjugated. An increase in unconjugated bilirubin in serum results from either overproduction, impairment of uptake, or impaired conjugation of bilirubin. An increase in conjugated bilirubin is due to decreased excretion into the bile ductules or backward leakage of the pigment. (See "Clinical aspects of serum bilirubin determination" and "Diagnostic approach to the patient with jaundice or asymptomatic hyperbilirubinemia".)
Unconjugated hyperbilirubinemia — Indirect hyperbilirubinemia may be observed in a number of disorders (table 3). These can be divided into disorders associated with bilirubin overproduction (such as hemolysis and ineffective erythropoiesis) and disorders related to impaired hepatic uptake/conjugation of bilirubin (such as Gilbert's disease, Crigler-Najjar syndrome, and the effects of certain drugs).
Hemolysis — Hemolysis can usually be detected by obtaining a reticulocyte count, haptoglobin, and examining the peripheral smear. Hemolytic disorders that cause excessive heme production may be either inherited or acquired. Inherited disorders include spherocytosis, sickle cell anemia, and deficiency of red cell enzymes such as pyruvate kinase and glucose-6-phosphate dehydrogenase. In these conditions the serum bilirubin rarely exceeds 5 mg/dL. Higher levels may occur when there is co-existent renal or hepatocellular dysfunction or in acute hemolysis such as a sickle cell crisis. (See "Approach to the diagnosis of hemolytic anemia in the adult".)
Acquired hemolytic disorders include microangiopathic hemolytic anemia (eg, hemolytic-uremic syndrome), paroxysmal nocturnal hemoglobinuria, and immune hemolysis. Ineffective erythropoiesis occurs in cobalamin, folate, and iron deficiencies.
Impaired hepatic uptake or conjugation — Impaired hepatic uptake or conjugation of bilirubin should be considered in the absence of hemolysis. This is most commonly caused by certain drugs (including rifampicin and probenecid) which diminish hepatic uptake of bilirubin, or Gilbert's syndrome (a common genetic disorder associated with unconjugated hyperbilirubinemia). Much less commonly, indirect hyperbilirubinemia can be caused by two other genetic disorders: Crigler-Najjar syndrome, types I and II.
Gilbert's syndrome affects approximately 3 to 7 percent of the population with white males predominating over females by a ratio of 2 to 7:1. Impaired conjugation of bilirubin is due to reduced bilirubin UDP glucuronosyl transferase activity. Affected patients have mild unconjugated hyperbilirubinemia with serum levels almost always less than 6 mg/dL. The serum levels may fluctuate and jaundice is often identified only during periods of illness or fasting. In an otherwise healthy adult with mildly elevated unconjugated hyperbilirubinemia and no evidence of hemolysis, the presumptive diagnosis of Gilbert's syndrome can be made without further testing. (See "Gilbert's syndrome and unconjugated hyperbilirubinemia due to bilirubin overproduction".)
Crigler Najjar type I is an exceptionally rare condition found in neonates and is characterized by severe jaundice (bilirubin >20 mg/dL) and neurologic impairment due to kernicterus. Crigler-Najjar type II is somewhat more common than Type I. Patients live into adulthood with serum bilirubin levels that range from 6 to 25 mg/dL. Bilirubin UDP glucuronosyl transferase activity is typically present, but greatly reduced. Bilirubin UDP glucuronosyl transferase activity can be induced by the administration of phenobarbital, which can reduce serum bilirubin levels in these patients. (See "Crigler-Najjar syndrome".)
Conjugated hyperbilirubinemia — Elevated conjugated hyperbilirubinemia is found in two rare inherited conditions: Dubin-Johnson syndrome and Rotor syndrome. (See "Inherited disorders associated with conjugated hyperbilirubinemia".)
Patients with both conditions present with asymptomatic jaundice typically in the second decade of life. The defect in Dubin-Johnson syndrome is altered excretion of bilirubin into the bile ducts while Rotor syndrome appears to be due to defective hepatic storage of bilirubin.
Dubin-Johnson and Rotor syndrome should be suspected in patients with mild hyperbilirubinemia (with a direct-reacting fraction of approximately 50 percent) in the absence of other abnormalities of standard liver function tests. Normal levels of serum alkaline phosphatase and gamma-glutamyltranspepetidase help to distinguish these conditions from disorders associated with biliary obstruction. Differentiating between these syndromes is possible, but clinically unnecessary, due to their benign nature.
ISOLATED ELEVATION OF THE ALKALINE PHOSPHATASE AND/OR GAMMA GLUTAMYL TRANSPEPTIDASE — Serum alkaline phosphatase is derived predominantly from the liver and bones, although other sources may contribute to serum levels in some settings. Women in the third trimester of pregnancy, for example, have elevated serum alkaline phosphatase due to an influx into blood of placental alkaline phosphatase. Individuals with blood types O and B can have elevated serum alkaline phosphatase after eating a fatty meal due to an influx of intestinal alkaline phosphatase. Infants and toddlers occasionally display transient marked elevations of alkaline phosphatase in the absence of detectable bone or liver disease. There are also reports of a benign familial occurrence of elevated serum alkaline phosphatase due to intestinal alkaline phosphatase. (See "Alkaline phosphatase and other enzymatic measures of cholestasis" and "Transient hyperphosphatasemia of infancy and early childhood".)
Alkaline phosphatase levels also vary with age. Alkaline phosphatase levels are generally higher in children and adolescents because of physiological osteoblastic activity. Levels may be up to three times higher than in healthy adults, with maximum levels in infancy and adolescence, coinciding with periods of maximum bone growth velocity (figure 1). Also, the normal serum alkaline phosphatase gradually increases from age 40 to 65, particularly in women. The normal alkaline phosphatase for an otherwise healthy 65-year-old woman is more than 50 percent higher than a healthy 30-year-old woman.
Determining the source of the alkaline phosphatase — The first step in the evaluation of an elevated alkaline phosphatase is to identify its source. Although electrophoretic separation on either polyacrylamide gel or sepharose are the most sensitive and specific ways to do this, these tests are not widely available. If gel electrophoresis is not available, either a 5'-nucleotidase or GGT should be obtained. These tests are usually elevated in parallel with the alkaline phosphatase in liver disorders, but are not increased in bone disorders. An elevated serum alkaline phosphatase with a normal 5'-nucleotidase or GGT should prompt an evaluation for bone diseases. Heat and urea denaturation of serum alkaline phosphatase are used by many laboratories, but are neither sensitive nor specific (algorithm 2). (See "Alkaline phosphatase and other enzymatic measures of cholestasis".)
Initial testing for alkaline phosphatase of hepatic origin — Chronic cholestatic or infiltrative liver diseases should be considered in patients in whom the alkaline phosphatase is determined to be of liver origin and persists over time. The most common causes include partial bile duct obstruction, primary biliary cirrhosis (PBC), primary sclerosing cholangitis, adult bile ductopenia, and certain drugs such as androgenic steroids and phenytoin. Infiltrative diseases include sarcoidosis, other granulomatous diseases, and less often unsuspected cancer metastatic to the liver.
Initial testing should include a right upper quadrant ultrasound (which can assess the hepatic parenchyma and bile ducts) and an antimitochondrial antibody (AMA), which is highly suggestive of PBC (algorithm 2). The presence of biliary dilatation suggests obstruction of the biliary tree. In patients with biliary dilatation or choledocholithiasis, an endoscopic retrograde cholangiopancreatogram (ERCP) should be done to identify the cause of obstruction and to allow for an intervention such as stone removal or stent placement. Patients with a positive AMA should have a liver biopsy to verify the diagnosis of PBC.
Patients in whom initial testing is unrevealing — We suggest a liver biopsy and either an ERCP or magnetic resonance cholangiopancreatogram (MRCP) if the AMA and ultrasound are both negative and the alkaline phosphatase is persistently more than 50 percent above normal for more than six months. If the alkaline phosphatase is less than 50 percent above normal, all of the other liver tests are normal, and the patient is asymptomatic, we suggest observation alone since further testing is unlikely to influence management [37].
Gamma glutamyl transpeptidase — Gamma glutamyl transpeptidase (GGT) is found in hepatocytes and biliary epithelial cells. In normal full-term neonates, serum GGT activity is six to seven times the upper limit of the adult reference range; levels decline and reach adult levels by 5 to 7 months of age [38]. GGT is sensitive for detecting hepatobiliary disease, but its usefulness is limited by its lack of specificity. Elevated levels of serum GGT have been reported in a wide variety of clinical conditions, including pancreatic disease, myocardial infarction, renal failure, chronic obstructive pulmonary disease, diabetes, and alcoholism. High serum GGT values are also found in patients taking medications such as phenytoin and barbiturates. (See "Alkaline phosphatase and other enzymatic measures of cholestasis".)
Some authorities have advocated using the GGT to identify patients with occult alcohol use. The reported sensitivity of an elevated GGT for detecting alcohol ingestion has ranged from 52 to 94 percent [20,39]. Its lack of specificity makes its use for this purpose questionable. A population-based study found that men with increased GGT levels who also had a hyperechogenic liver by ultrasound (suggesting the presence of steatosis) has increased all-cause mortality rates but more data are needed [40].
We suggest GGT be used to evaluate elevations of other serum enzyme tests (eg, to confirm the liver origin of an elevated alkaline phosphatase or to support a suspicion of alcohol abuse in a patient with an elevated AST and an AST:ALT ratio of greater than 2:1). An elevated GGT with otherwise normal liver tests should not lead to an exhaustive work-up for liver disease.
EVALUATION OF PATIENTS WITH SIMULTANEOUS ELEVATION OF SEVERAL LFTS — The previous sections have discussed the evaluation of isolated elevations of LFTs. The following sections will focus upon common presentations of patients who have elevation of several of the tests simultaneously. As discussed above, it is helpful to attempt to divide this group of patients into those with a predominantly hepatocellular process and those with a predominantly cholestatic process, although the distinction is not always possible. Patients with a predominantly cholestatic pattern may be further divided into those with intra- or extrahepatic cholestasis (table 4).
The degree of aminotransferase elevation can occasionally help in differentiating between hepatocellular and cholestatic processes. While ALT and AST values less than eight times normal may be seen in either hepatocellular or cholestatic liver disease, values 25 times normal or higher are seen primarily in hepatocellular diseases. On the other hand, patients with jaundice from cirrhosis may have normal or only slight elevations of the aminotransferases. (See "Patterns of plasma aspartate and alanine aminotransferase levels with and without liver disease".)
Predominantly hepatocellular pattern with jaundice — Common hepatocellular diseases that can cause jaundice include viral and toxic hepatitis (including drugs, herbal therapies and alcohol) and end-stage cirrhosis from any cause (table 5). Wilson's disease should be considered in young adults.
Autoimmune hepatitis predominantly occurs in young to middle-aged women (although it may affect men and women of any age) and should particularly be considered in patients who have other autoimmune diseases.
Alcoholic hepatitis — Alcoholic hepatitis can be differentiated from viral and toxin related hepatitis by the pattern of the serum aminotransferases. Patients with alcoholic hepatitis typically have an AST:ALT ratio of at least 2:1. The AST rarely exceeds 300 U/L. In contrast, patients with acute viral hepatitis and toxin related injury severe enough to produce jaundice typically have aminotransferases greater than 500 U/L with the ALT greater than or equal to the AST.
Viral hepatitis — Patients with acute viral hepatitis can develop jaundice. Appropriate testing for suspected acute viral hepatitis includes a:
Hepatitis A IgM antibody
Hepatitis B surface antigen
Hepatitis B core IgM antibody
Hepatitis C viral RNA
Patients with acute hepatitis C are usually asymptomatic. As a result, acute hepatitis C is an uncommon cause of acute viral hepatitis that is clinically evident. Nevertheless, testing for acute HCV is reasonable and should be performed by requesting an assay for serum hepatitis C viral RNA since hepatitis C antibody may take weeks to months to become detectable. (See "Screening for and diagnostic approach to hepatitis C virus infection".)
Toxic hepatitis — Drug induced hepatocellular injury can be classified either as predictable or unpredictable. Predictable drug reactions are dose-dependent and affect all patients who ingest a toxic dose of the drug in question. The classic example is acetaminophen hepatotoxicity. Unpredictable, or idiosyncratic, drug reactions are not dose dependent and occur in a minority of patients. Virtually any drug can cause an idiosyncratic reaction. As discussed above, features suggesting drug toxicity include lack of illness prior to ingesting the drug, clinical illness or biochemical abnormalities developing after beginning the drug, and improvement after the drug is withdrawn.
Environmental toxins are also an important cause of hepatocellular injury. Examples include industrial chemicals such as vinyl chloride, herbal preparations containing pyrrolizidine alkaloids (Jamaica bush tea), and the mushrooms Amanita phalloides or verna containing highly hepatotoxic amatoxins.
Shock liver (ischemic hepatitis) — Patients who have a prolonged period of systemic hypotension (such as following a cardiac arrest or patients with severe heart failure) may develop ischemic injury to several organs including the liver. Striking increases in serum aminotransferases (exceeding 1000 IU/L or 50 times the upper limit of normal) and lactic dehydrogenase may be seen [41-43]. Patients may also develop jaundice, hypoglycemia, and hepatic synthetic dysfunction. The majority of patients have concomitant deterioration of renal function. The prognosis depends mostly upon the underlying condition. Hepatic function usually returns to normal within several days of the acute episode. (See "Ischemic hepatitis, hepatic infarction, and ischemic cholangiopathy".)
Wilson's disease — Patients with Wilson's disease can occasionally present with acute and even fulminant hepatitis. The diagnosis should be considered in patients younger than 40, particularly those who have concomitant hemolytic anemia. (See "Pathogenesis and clinical manifestations of Wilson disease" and "Diagnosis of Wilson disease".)
Autoimmune hepatitis — Patients with autoimmune hepatitis can present with acute and even fulminant hepatitis. The diagnosis is established by the clinical setting, exclusion of other causes, serologic testing, and in some cases a liver biopsy. (See "Clinical manifestations and diagnosis of autoimmune hepatitis".)
Predominantly cholestatic pattern — The first step in evaluating patients whose LFT pattern predominantly reflects cholestasis is to determine whether the cholestasis is due to intra- or extrahepatic causes (table 4). However, the distinction is not always straightforward since the history, physical examination, and laboratory tests are often not helpful.
A reasonable first step is to obtain a right upper quadrant ultrasound, which has a number of advantages compared to other imaging modalities. It is inexpensive, does not expose the patient to ionizing radiation, and can detect dilation of the intra- and extrahepatic biliary tree with a high degree of sensitivity and specificity. (See "Ultrasonography of the hepatobiliary tract".)
The absence of biliary dilatation suggests intrahepatic cholestasis, while the presence of biliary dilatation indicates extrahepatic cholestasis. False negative results occur in patients with partial obstruction of the common bile duct or in patients with cirrhosis or primary sclerosing cholangitis where scarring prevents the intrahepatic ducts from dilating.
Extrahepatic cholestasis — Although ultrasonography may indicate extrahepatic cholestasis, it rarely identifies the site or cause of obstruction. The distal common bile duct is a particularly difficult area to visualize by ultrasound because of overlying bowel gas. Appropriate next tests include computerized tomography (CT) and endoscopic retrograde cholangiopancreatography (ERCP). CT scanning is better than ultrasonography for assessing the head of the pancreas and for identifying choledocholithiasis in the distal common bile duct, particularly when the ducts are not dilated.
Choledocholithiasis is the most common cause of extrahepatic cholestasis. The clinical presentation can range from mild right upper quadrant discomfort with only minimal elevations of the enzyme tests to ascending cholangitis with jaundice, sepsis, and circulatory collapse. Choledocholithiasis is usually associated with elevation of the serum alkaline phosphatase out of proportion to the aminotransferases, although elevation of aminotransferases to greater than 1,000 IU/L have been described [44].
ERCP is the gold standard for identifying choledocholithiasis. It is performed by introducing a side-viewing endoscope orally into the duodenum. The ampulla of Vater is visualized and a catheter is advanced through the ampulla. Injection of dye allows for the visualization of the common bile duct and the pancreatic duct. The success rate for cannulation of the common bile duct ranges from 80 to 95 percent depending on the operator's experience. In addition to its diagnostic capabilities, ERCP allows for therapeutic interventions including the removal of common bile duct stones and the placement of stents.
In patients in whom ERCP is unsuccessful, transhepatic cholangiography can provide the same information. Magnetic resonance cholangiopancreatography (MRCP) is a rapidly developing, non-invasive technique for imaging the bile and pancreatic ducts, which may replace ERCP as the initial diagnostic test in cases where the need for intervention is felt to be small. (See "Magnetic resonance cholangiopancreatography".) Choledocholithiasis can also be detected with endoscopic ultrasound. (See "Endoscopic ultrasound in patients with suspected choledocholithiasis".)
Malignant causes include pancreatic, gallbladder, ampullary, and cholangiocarcinoma. The latter is most commonly associated with PSC and is exceptionally difficult to diagnose because its appearance is often identical to PSC. Pancreatic, gallbladder, and cholangiocarcinoma are rarely resectable and have poor prognoses. Ampullary carcinoma has the highest surgical cure rate of all the tumors that present as painless jaundice. Hilar lymphadenopathy due to metastases from other cancers may cause obstruction of the extrahepatic biliary tree.
Patients with primary sclerosing cholangitis may have clinically important strictures limited to the extrahepatic biliary tree. Patients who have a dominant stricture can be effectively be managed with serial endoscopic dilatations.
Chronic pancreatitis uncommonly causes strictures of the distal common bile duct where it passes through the head of the pancreas. (See "Complications of chronic pancreatitis".)
AIDS cholangiopathy (usually due to infection of the bile duct epithelium with CMV or Cryptosporidium) has a cholangiographic appearance similar to PSC. Patients usually present with greatly elevated serum alkaline phosphatase levels (around 800 IU/L) with a normal or near normal bilirubin level. Thus, these patients do not typically present with jaundice. (See "AIDS cholangiopathy".)
Intrahepatic cholestasis — The list of possible causes of intrahepatic cholestasis is long and varied (table 4). A number of conditions that typically cause a hepatocellular pattern of injury can also present as a cholestatic variant. As examples, hepatitis B and C can cause a cholestatic hepatitis (fibrosing cholestatic hepatitis), which has histological features which mimic large duct obstruction. This disease variant has been reported in patients who have undergone solid organ transplantation. (See "Hepatitis C virus infection and renal transplantation".) Hepatitis A, alcoholic hepatitis, EBV, and CMV can also present as cholestatic liver disease.
Drug induced cholestasis usually is reversible after elimination of the offending drug, although it may take many months for cholestasis to resolve. Drugs most commonly associated with cholestasis are the anabolic and contraceptive steroids. Cholestatic hepatitis has also been reported with chlorpromazine, imipramine, tolbutamide, sulindac, cimetidine, erythromycin estolate, trimethoprim-sulfamethoxazole, and penicillin based antibiotics such as ampicillin and dicloxacillin. Rarely drug induced cholestasis may be chronic and associated with progressive fibrosis. This pattern has been described with chlorpromazine and prochlorperazine. (See "Drugs and the liver: Patterns of drug-induced liver injury".)
Primary biliary cirrhosis is a disease predominantly of middle-aged women in which there is a progressive destruction of interlobular bile ducts. The diagnosis is made by the presence the antimitochondrial antibody which is found in 95 percent of patients. (See "Clinical manifestations, diagnosis, and natural history of primary biliary cirrhosis".)
Primary sclerosing cholangitis (PSC) is characterized by the destruction and fibrosis of larger bile ducts. The disease may involve only the intrahepatic ducts and present as intrahepatic cholestasis. However, in 65 percent of patients with PSC, both intra- and extrahepatic ducts are involved. The diagnosis of PSC is made by ERCP in which the pathognomonic findings are multiple strictures of bile ducts with dilatations proximal to the strictures. The majority of patients with PSC have inflammatory bowel disease. (See "Clinical manifestations and diagnosis of primary sclerosing cholangitis".)
The vanishing bile duct syndrome and adult bile ductopenia are rare conditions in which there are a decreased number of bile ducts seen in liver biopsy specimens. This picture is seen in patients who develop chronic rejection after liver transplantation, in rare cases of sarcoidosis, in patients taking certain drugs including chlorpromazine, and idiopathically. There are also familial forms of intrahepatic cholestasis. Benign recurrent cholestasis is an autosomal recessive disease marked by recurrent, self-limited episodes of jaundice and pruritus. Cholestasis of pregnancy occurs in the second and third trimesters and resolves after delivery. (See "Inherited disorders associated with conjugated hyperbilirubinemia".)
Other causes of intrahepatic cholestasis include total parenteral nutrition, non-hepatobiliary sepsis, benign post-operative cholestasis, and a paraneoplastic syndrome (Stauffer's syndrome) associated with a number of different malignancies, including Hodgkin lymphoma, medullary thyroid cancer, hypernephroma, renal sarcoma, T-cell lymphoma, prostate cancer, and several gastrointestinal malignancies.